In spite of the early discovery of insulin and its subsequent wide-spread use in the treatment of diabetes, and the later discovery and use of sulfonylureas (e.g. chlorpropamide, tolbutamide, acetohexamide, tolazamide) and biguanides (e.g. phenformin) as oral hypoglycemic agents, the treatment of diabetes remains less than satisfactory. The use of insulin, necessary in a high percentage of diabetics where available synthetic hypoglycemic agents are not effective, requires multiple daily, usually self, injection. Determination of the proper dosage of insulin requires frequent estimations of the sugar in the urine or in the blood. The administration of an excessive dose of insulin causes hypoglycemia, with effects ranging from mild abnormalities in blood glucose to coma, or even death. Where effective, synthetic hypoglycemic agents are preferred over insulin, being more convenient to administer and less prone to cause severe hypoglycemic reactions. However, the clinically available hypoglycemics are fraught with other toxic manifestations which limit their use. In any event, where one of these agents may fail in an individual case, another may succeed. The need for additional hypoglycemic agents, which may be less toxic or succeed where others fail, is clearly evident.
In addition to the hypoglycemic agents cited above, a variety of other compounds have been reported to possess this type of activity, including 5-methylpyrazole-3-carboxylic acid [Smith, et al., J. Med. Chem. 8, 350 (1965)], 3-methylisoxazole-5-carboxylic acid [Dulin and Gerritsen, Proc. Soc. Expt. Biol. Med. 121, 777 (1966)], 1-methyl-4-(5-methyl-3-pyrazolyl)pyridinium iodide [Dulin et al., Proc. Soc. Expt. Biol. Med. 118, 499 (1965)], 1-methyl-4-(3-methyl-5-isoxazolyl)pyridinium chloride [Bauer et al., J. Med. Chem. 11, 984 (1968)], 2-carboxypyrazine [Dulin and Gerritsen, Metab. Clin. Exp. 18, 214 (1969)], a series of hexahydroindeno(1,2-c)pyrroles and dialkylaminomethylindans [Lahiri and Pathak, J. Pharm. Sci. 57, 1013 (1968)], methylenecyclopropylacetic acid and 4-pentenoic acid [Corredor et al., Proc. Nat. Acad. Sci. U.S. 58, 2299 (1967)].
In many cases the compounds of the present invention are known from the literature:
5-Methoxyfuran-2-carboxylic acid [Manly and Amstutz, J. Org. Chem. 21, 516 (1956)];
5-Ethoxyfuran-2-carboxylic acid [Manly and Amstutz, loc. cit.];
5-Methoxythiophene-2-carboxylic acid [Sice, J. Am. Chem. Soc. 75, 3697 (1953)];
5-Phenoxyfuran-2-carboxylic acid [Manly and Amstutz, loc. cit.];
5-Benzylfuran-2-carboxylic acid [Mndzhoyan et al., Doklady Akad. Nauk Armyan. S.S.R. 25, 133 (1957); Chem. Abstr. 52, 6306e; Tsukervanik and Galust'yan, Dokl. Akad. Nauk. Uz. S.S.R. 20, 26 (1963); Chem. Abstr. 59, 6341a; potential plant stimulant].
5-Benzylfuran-3-carboxylic acid [Fr. patent 1,578,377; insecticide];
5-Benzylthiophene-2-carboxylic acid [MacDowell and Patrick, J. Org. Chem. 32, 2441 (1967)];
3-Phenylthiomethylthiophene-2-carboxylic acid [Tagawa and Ueno, Chem. Pharm. Bull. 26, 1384 (1978); synthetic intermediate in synthesis of non-steroidal antiinflammatory agents];
5-Phenylthiofuran-2-carboxylic acid [Manly and Amstutz, loc. cit.; Kada et al., Collection Czech. Chem. Commun. 41, 2571 (1976)];
5-(4-Methylphenylthio)furan-2-carboxylic acid [Kada et al., loc. cit.];
5-(4-Methoxyphenylthio)furan-2-carboxylic acid [Kada et al., loc. cit.];
5-(4-Chlorophenylthio)furan-2-carboxylic acid [Kada, et al., loc. cit.];
5-Bromofuran-2-carboxylic acid [Whittaker, Rec. Trav. Chim. 52, 352 (1933); German Patent 1,172,938 (Chem. Abstr. 61, 16706h); food preservative];
5-Bromofuran-3-carboxylic acid [Gilman and Burtner, J. Am. Chem. Soc. 55, 2903 (1933)];
2-Bromofuran-3-carboxylic acid [Gilman and Burtner loc. cit.];
5-Bromothiophene-2-carboxylic acid [Fournari et al., Bull. Soc. Chim. Fr., 4115 (1967); Parker, U.S. Pat. No. 4,011,333; intermediate for hypolipidemic agents];
5-Bromothiophene-3-carboxylic acid [Fournari et al., loc. cit.];
2-Bromothiophene-3-carboxylic acid [Fournari et al., loc. cit.]; Gronowitz and Pettersson, J. Heterocycl. Chem 13, 1099 (1976);
5-Chlorofuran-2-carboxylic acid [Nazarova and Babaev, Zh. Obstrch. Khim. 32, 723 (1962); Chem. Abstr. 58, 5606g];
2-Chlorofuran-3-carboxylic acid [Roques et al., Bull. Soc. Chim. Fr., 242 (1971)];
5-Chlorothiophene-2-carboxylic acid [Gronowitz and Pettersson, loc. cit; Parker, loc. cit.; intermediate for hypolipidemic agents];
5-Chlorothiophene-3-carboxylic acid [Sone et al., Nippon Kagaku Zasshi 92, 1193 (1971); Chem. Abstr. 76, 153468c]; and
2-Chlorothiophene-3-carboxylic acid [Dafgard et al., Acta. Pharm. Suec. 11, 309 (1974); Chem. Abstr. 81, 105148e].
The pharmaceutical use of these compounds, in particular their use as hypoglycemic agents, however, is novel.